Matrix metalloproteinase-7 (matrilysin) controls neutrophil egress by generating chemokine gradients

Mei Swee^*^,, Carole L. Wilson, Ying Wang^*^,, John K. McGuire^*^,^, and William C. Parks^*^,^,1

^* Center for Lung Biology and Institute for Stem Cell and Regenerative Medicine and Departments of
Medicine (Pulmonary and Critical Care Medicine),
Pathology, and
Pediatrics (Critical Care Medicine), University of Washington, Seattle, Washington, USA

¹Correspondence: Center for Lung Biology, University of Washington, 815 Mercer Street, Seattle, WA 98109, USA. E-mail: parksw{at}u.washington.edu

Matrilysin [matrix metalloproteinase 7 (MMP7)] is induced bymucosal injury of many tissues. To assess function of this proteinase,we subjected wild-type and Mmp7^–/– mice to acutecolon injury. When matrilysin expression was increasing, 73%of wild-type mice died, whereas only 32% of Mmp7^–/–mice succumbed. Although re-epithelialization was delayed inMmp7^–/– mice, overall injury did not differ markedlybetween genotypes. We hypothesized that differences in acuteinflammation caused increased mortality in wild-type mice. Indeed,whereas overall neutrophil influx into tissue was similar inwild-type and Mmp7^–/– mice, their location and extentof migration differed between genotypes. Neutrophils were dispersedthroughout the mucosa and within the lumen of wild-type mice,but these leukocytes were largely confined to the submucosain Mmp7^–/– mice. The levels of neutrophil chemokines,keratinocyte-derived chemokine and MIP-2, increased in the colontissue of both genotypes, but these factors were detected onlyin lumenal lavages of wild-type mice. Our findings indicatethat matrilysin mediates beneficial and deleterious effectsin response to injury. On one hand, it promotes re-epithelialization,but it also controls the transepithelial influx of neutrophils,which if excessive, can lead to tissue damage.

Key Words: inflammation • epithelium • protease